umpire trial use of a multidrug pill in reducing

UMPIRE trial Use of a Multidrug Pill In Reducing cardiovascular Events

Simon Thom; UMPIRE Collaborative group

Cardiovascular combination pharmacotherapy summit,

Melbourne, 8 May 2014

Disclosure statement of financial interest

• Grant / research support

• Dr Reddy’s Labs Ltd

Within the past 2 years, I have had a financial arrangement with the healthcare related company listed below.

Affiliation / financial relationship Company

Travel funds via my employing institution (Imperial College London) in relation to the UMPIRE trial.

Simon Thom

Primary objectives

• To test the hypothesis that a FDC-based strategy (a “polypill”) for delivery of preventive medications (aspirin, statin & 2 BP lowering drugs) compared with usual care might improve:

– Adherence to indicated therapy

– Systolic BP

– LDL-cholesterol,

at the end of the study,

in people with (or at high risk of) CVD.

UMPIRE trial

Patients with established CVD; or at ≥ 15% 5-year risk (n = 2000, India & Europe)

Treatment strategy based on fixed dose combination

Continued “usual care”

Randomisation

24 months or End of Study *

1 month, 6 month, 12 month, 18 month follow-up

PROBE design (c/o IMPACT & Kanyini-GAP)

inclusion exclusion: contraindications or known intolerance of FDC components * 12 months after last randomisation (range 12 – 24)

Methods

• Adherence: self-reported use of [antiplatelet, statin and ≥2 BP lowering drugs]

• BP: electronic Omron 705CP II + printer

• Cholesterol & blood tests: local laboratories

Randomisation

• FDC : usual care, 1 : 1 (web-based)

• Stratified by presence or absence of established CVD

• 28 in India

• 3 in Europe (Dublin, London, Utrecht)

Trial sites

• June 2010 – July 2011

Recruitment

Fixed dose combinations, x 2

Version 1 Version 2

aspirin 75mg

simvastatin 40mg

lisinopril 10mg

atenolol 50mg

aspirin 75mg

simvastatin 40mg

lisinopril 10mg

hydrochlorothiazide 12.5mg

Usual care

As per local clinical guidelines.

Study treatments

Physicians could add additional medications, stop the FDC & begin treatment with separate medications, or switch FDC version.

Participants in the FDC group were dispensed study FDC free of charge from their trial centre. Participants in the usual care group acquired their medications subject to local payments or exemptions; 966 participants (48%) were exempt from medication charges.

Patients screened, 2138

Randomised, 2004

Ineligible, 134

FDC, 1002 Usual care, 1002

Visits, 994 Visits, 993





Visits, 955 Medication data, 945 BP, 927; LDL, 908

Visits, 952 Medication data, 947 BP, 913; LDL, 888

Baseline

Month 1

Month 18

Month 6

Month 12

Month 24

End of study

UMPIRE, Consort diagram

15 months Median follow-up

FDC (N = 1002)

Usual care (N = 1002)

Age 62.1 (10.4) 61.6 (10.8)

Male 81 % 82 %

SBP (mmHg) 137.0 (21.3) 137.7 (21.1)

LDL-cholesterol (mmol/L) 2.3 (0.8) 2.4 (0.9)

Medical history

Established CVD 88 % 88 %

Diabetes mellitus 28 % 28 %

Current drug treatment

Antihypertensive treatment

None 7.6 % 6.6 %

1 BP drug 26.5 % 22.5 %

≥2 BP drugs 65.9 % 71.0 %

Statin 88.0 % 87.6 %

Anti-platelet drug 91.8 % 91.0 %

All indicated medications 59.7 % 63.4 %

Baseline characteristics

Indicated medications = statin + anti-platelet + ≥2 anti-hypertensive drugs

Results

Outcome

FDC

(N = 1002)

Usual care

(N = 1002)

Treatment

Effect (95% CI)

P-value

Adherence (%) 86% (1%) 65% (2%) 1.33 (1.26; 1.41) <.0001

Systolic BP (mmHg) 129.2 (0.5) 131.7 (0.5) -2.6 (-4.0; -1.1) 0.0005

LDL-cholesterol (mmol/L) 2.18 (0.02) 2.29 (0.02) -0.11 (-0.17; -0.05) 0.0005

- at end of study

Effects on primary outcomes

1 mmol/L = 38.67 mg/dl cholesterol

Adherence to indicated medications by treatment group

Indic

ate

d m

edic

ations (

%)

1002 1002

977 978

935 925

524 522

34 36

FDC

Usual Care

Numbers assessed

Adherence by pre-specified subgroups

Risk ratio (95% CI)

p-value

CVD risk

Established CVD 1.29 (1.22, 1.36)

<0.001 ≥ 15% 5yr risk 1.93 (1.51, 2.47)

Reporting all 4 components at baseline

Yes 1.04 (1.01, 1.08)

<0.001 No 3.35 (2.74, 4.09)

Continent

Europe 1.27 (1.18, 1.37)

0.072 India 1.40 (1.30, 1.51)

1/4 1 4

Favours usual care

Favours FDC

Risk ratio

Outcome FDC

(N = 1002)

Usual care

(N = 1002)

Treatment

Effect (95% CI)

P-value

Adherence at 12 months (%) 88% (1%) 65% (2%) 1.36 (1.29; 1.43) <.0001

Diastolic BP (mmHg) 72.8 (0.3) 75.2 (0.3) -2.5 (-3.3; -1.6) <.0001

Total cholesterol (mmol/L) 4.06 (0.03) 4.12 (0.03) -0.07 (-0.14; 0.01) 0.08

HDL-cholesterol (mmol/L) 1.14 (0.01) 1.13 (0.01) 0.01 (0.00; 0.03) 0.1

Triglycerides (mmol/L) 1.61 (0.03) 1.57 (0.03) 0.04 (-0.03; 0.11) 0.3

Creatinine (µmol/L) 94.6 (0.6) 91.9 (0.6) 2.7 (1.0; 4.4) 0.002

Quality of life (EQ5D; VAS) 76.1 (0.56) 73.7 (0.57) 2.43 (0.87; 3.99) 0.002

Cardiovascular events (n) 50 (5%) 35 (3.5%) 1.45 (0.94; 2.24) 0.09

Secondary outcomes

Cholesterol 1 mmol/L = 38.67 mg/dl; Triglyceride 1 mmol/L = 88.6 mg/dl; Creatinine I µmol/L = 0.0113 mg/dl.

Conclusions

• An FDC strategy including aspirin, statin & 2 BP lowering drugs improves adherence, BP & cholesterol in patients with established CVD & those at high risk.

• The effect, a 33% increase in adherence over a median interval of 15 months, was evident in a trial population with an unusually high reported use of indicated medication at the outset.

• The greatest effect, a 3-fold increase in adherence, was seen in those non-adherent at the outset.

• The effect on adherence was similar in those exempt or not exempt from medication charges (post hoc analysis).

Thanks for

your attention

Investigators

Michiel Bots (UMCU, Utrecht)

Raghu Cidambi (Dr Reddy’s, Hyderabad)

Jane Field (Imperial College London)

Rick Grobbee (UMCU, Utrecht)

Anushka Patel ( George Inst. Hyderabad)

Neil Poulter (Imperial College London)

D. Prabhakaran (CCDC, Delhi)

K. Srinath Reddy (PHFI, Delhi)

Anthony Rodgers (George Inst. Sydney)

Alice Stanton (RCSI, Dublin)

Simon Thom (Imperial College London)

Statisticians

Laurent Billot (George Inst. Sydney)

Severine Bompoint (George Inst. Sydney)

http://www.spacecollaboration.org

SPACE (Single Pill Against Cardiovascular Events)

http://clinicaltrials.gov/ct2/show/NCT01057537?term=umpire&rank=1

http://www.ctri.in/Clinicaltrials/index.jsp

Systolic blood pressure by treatment group

Systo

lic B

P (

mm

Hg) Usual Care

FDC

Numbers assessed

LDL-cholesterol by treatment group

LD

L-chole

ste

rol (m

mol/

L)

Usual Care

FDC

Numbers assessed

SAE category FDC

(N = 1002)

Usual care

(N = 1002)

Total 154 142

Patients with at least one SAE 118 (11.8%) 102 (10.2%)

Cardiac disorders 42 (4.2%) 27 (2.7%)

Infections & infestations 16 (1.6%) 10 (1.0%)

Neoplasms benign & malignant 13 (1.3%) 11 (1.1%)

Vascular disorders 11 (1.1%) 12 (1.2%)

Nervous system disorders 9 (0.9%) 13 (1.3%)

Gastrointestinal disorders 10 (1.0%) 11 (1.1%)

Other 36 (3.6%) 40 (4%)

Serious adverse events

umpire trial use of a multidrug pill in reducing

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